Diketopregnanespirothiazolidine



2,776,967 mKEToPREGNANEsPInoTI-uAzoLinmE Gunther S. Fonlren and .lohn A.Hogg, Kalamazoo Tiownship, Kalamazoo County, Mich assignors to The Upjohn Company, Kalamazoo, Mich, a corporation Michigan No Drawing.Application September 8, 1955, Serial No. 533,236

7 Claims. (Cl. zen-239.5

This invention relates to new organic compounds and is particularlydirected to lllgZO-diketoprgnane-3-spiro (2- thiazolidine-4-canboxylicacid) either as the free acid or as a salt thereof and in both theSfi-(normai) and Sec (allo) rfiorms.

it is an object of the invention to provide novel physio- I A S O 1 Vand which can exist and can be used for the purposes of the invention ineither the 5B- or Set-form and in the form of the free acid or saltthereof with a pharmacologica'lly acceptable cation such as ammonium,sodium, potassium, lithium, and like alkali metal cations, calcium,strontium, and magnesium and like alkaline earth metal cations, and thecations of organic bases such as basic amines, as lfOl example, mono-,di-, and trimethylamines, mono-, di-, and triethylamines, mono-, di-,and tr-iisopnopylamines, ethyldimethylamine, benzyldiethylamine,cyclohexylamine, dibenzylamine, and like N, N+dibenzy1- ethylenediamine, bis-:ortho-methoxy-N-methyl orthophenylisopropylamine,methoxyphenylisopropylamine, lower-aliphatic, l-ower-cycloaliphatic, andiowenaraliph'atic amines up to and including about eight carbon atoms;

heterocyclic amines such as piperidine, morpholine, pynrolidine,piperazine, and the lower-alkyl derivatives thereof, such asl-methylpiperidine, 4-ethylmonpholine, l-isopropylpyrrolidine,1,4-dimethylpiperazine, l-n buty lpiperidine, 2-methy1piperidine,1-1ethyl-2-methylpiperidine, mono-, di-, and tniethanolamines,ethyldiethano'lamine, n-butylmonoethanolamine, 2-amino-'1-butanol,

2 amino 2 ethyl- 1, 3 propanediol, 2 amino 2- methyl-l-propanol, tris(hydnoxymethyl) aminomethane, phenylmonoethanolamine,p-tertiaryamylphenyldiethanol amine, and galactamine, N-methylglucamine, N methyl glucosamine, ephedrine, phenylephrine, epinephrine,procaine, and the like.

The compounds of the invention are characterized by theWater-solnbiliz-ing canboxy-l or canboxylate groups linked to the31position of a pregnane-l l,20-dione through a thiazolidi-ne group. Thenormal compounds of the invention have the advantages over the parentsteroid of water-so'1u l: ili ty and more prolonged action. \Theprolonged action is a surprising and unexpected effect because theintroduction of water-solubilizing groups in active steroids has beenobserved heretofore to speed up the desired pharmacodynamic action. Thecompounds of the invention, therefore, have entirely new andunforeseeable pharmacodynamic activity. For example, when equal doses(two milligrams) are administered intraperitoneal-ly to rats, anesthesiais induced in two to five minutes with 5/3-pregnane-3,11-20-trione andthe animals sleep about thirty minutes whereas with 11,20-diketopregnane 3 spiro( 2 thiazolidine 4 carboxylic acid), sodium salt,no effect was observed tor twenty to thirty minutes and the animals thenwent into a light sleep and slept for about two hours. The same relative'eiifects were obtained when the two compounds were administeredintravenously. The allo compounds of the invention have activity similarto the activity of the normal compounds of the invention which isentirely unexpected in view of the lack of activity in the parentcompound, Sm-pregnane-SJQ, ZO-trione.

The invention may be more fully understood by the foliowing exampleswhich are illustnative only and not to be construed as limiting.

Example 1. 11,20 diketo 5B pregnllne 3 spir0 (2-thiazolidine-4-carboxylic free acid) 0A /\5 tL B BIO-C NE A solutionof4.'39 grams (27.9 millimoles) of cysteine hydrochloride and 2.8 grams(about 28 millimoles) of potassium acetate in lforty milliliters ofwater was diluted to eighty milliliters volume with percent ethanol andadded to a solution of nine grams (27.2 millimoles) of.iflpregnane-B,lil,20-trione in 350 milliliters of 95 percent ethanol.The mixture was stirred at room temperature overnight, then refluxedwith stirring for about eight hours, allowed to stand overnight at roomternpenature and the product then recovered by filtration. After washingwith water and drying the material in a vacuum oven at about fiftydegrees centigrade there was obtained 7.3 grams of crude11,20-diketo-5fl-pregnane-3-spiro(2-thiazolidine-4-car'hoxylic freeacid),, melting point 155-160 degrees centigrade with decomposition.

Example 2. 11,20 diketo 5B pregnane 3 spir0(2- thiaz0lidine-4-carb0xylicacid), sodium salt S tL H The free spiro acid (7.3 grams) of Example 1was slurried in fifty milliliters of water and about milliliters ring,the course of the addition being followed with a pH meter, theelectrodes of which were placed in the reaction mixture. Addition ofalkali was stopped at pH 8.1. The cloudy solution was-filtered through alied of diatomaceousearth and 'then-Was lyophilizedto give 7.1 grams (90percent, based on unrecovered pregnanc- 3,1 1,20-trione)- of the desiredsodium salt. The infrared spectrum was consistent with the structuregivenabove.

Example 3. 11,20 dikelo 50c pregnane 3 spir(2- tliiazolidine-I-carboxylic free acid To a solution formed by heating 3.30 grams (tenmillimoles) of Sa-pregnane-SJI, 20-trione in 100 milliliters of absoluteethanol to reflux with stirring, there was added 1.57 grams (tenmillimoles) of cysteine hydrochloride and one gram (10+ millimoles) ofanhydrous potassium acetate dissolved in fifteen milliliters of waterand fifteen milliliterslof ethanol. The reaction mixture thus preparedwas then refluxed with stirring for twenty hours. A thick precipitateformed after five minutes. After cooling in an ice bath for severalhours with stirring, filtering, triturating with water and drying inair, there was obtained 3.19 grams (73.8 percent of theory) of 11,20diketo m pregnane 3 spiro(2 thiazolidine-4-carboxylic free acid.

Example 4. 11,20 --diketo 50c pregnane 3 spir0(2-thiaz0lidine-4-carb0xylic acid), sodium alt The free spiro acid (3.19grams) of Example 3 was slurried in fifty milliliters of water and about65 milliliters of one-tenth normal sodium hydroxide added with stirring.The pH rose to about 11. The cloudy solution was centrifuged tocoagulate the gelatinous precipitate. The supernatant was decanted andthe residue lyophilized to yield 2.6 grams of the desired sodium salt.The infrared spectrum was eonsistent with the structure givenabove.

In place of sodium hydroxide there may be substituted appropriate basesto obtain the potassium, lithium, ammonium, calcium, strontium,magnesium, basic amines such as mono-, di-, and trimethylamines, mono,di-, and triethylamines, mono-, di-, and triisopropylamines,ethyldimethylamine, benzyldiethylamine, cyclohexylamine, dibenzylamine,and like N,N-dibenzylethylene diamine, bis-ortho-methoxy-N-methylortho-phenylisopropylamine, methoxyphenylisopropylamine,lower-aliphatic, lowercycloaliphatic, and lower-aralip'hatic amines upto and including about eight carbon atoms; heterocycli'c amines such aspiper-idine, morpholine, pyrrolidine, piperazine,

. and the lower-alkyl derivatives thereof, such as l-methylpiperidine,4-ethylmorpholine, l-isopropylpyrrolidine, 1,4-dimethylpiperazine,l-n-butylpiperidine, Z-methylpiperidine, 1ethyl-2-methylpiperidine,mono-, di-, and triethanolamines, ethyldiethanolamine, nbutylmonoethanolamine, Z-amino-l-butanol, Z-amino-Z-ethyl-LB-propanediol, Z-amino-Z-methyl-l-propanol, tris (hydroxymethyl)aminomethane, phenylmonoethanolamine, ptertiaryamylphenyldiethanolamine,and galactarnine, N-methylglucamine, N-methyl glycosamine, ephedrine,phenylephrine, epinephrine, procaine, and the like salts.

The novel compounds of this invention can be administered orally orparenterally in such dosage forms, tablets, injectables, and elixirs, asare commonly ern ployed with central nervous system depressants. Theycan be combined. with faster acting drugs such aspregnane-3,ll,20-trione and 2'1-hydroxypregnane-3,20-dione hydrogensuccinate, sodium salt, to give products having both: immediate andprolonged action.

It is to be understood that the invention is not to be limited. to theexact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art, and the invention is therefore to be limited only by the scopeof the appended claims.

We claim:

1. 11,20 diketopregnane 3 spiro(2 thiazolidine- 4-carboxylic acid).

2. 11,20 diketopregnane 3 spiro(2 thiazolidine 4-carboxylic acid),sodium salt.

3. 11,20 diketo 5B pregnane 3 spiro(2-thiazolidine-4-carboxylic freeacid).

4. 11,20 diketo 5/5 pregnane 3 spiro(2 thiazolidine-4-carboxylic acid),sodium salt.

5. 11,20 diketo 5a pregnane 3 spiro(2 -'thiazo1idine-4-carboxylic freeacid).

6. 11,20 diketo 5oz pregnane 3 spiro(2 thiazolidine-4'carboxylic acid),sodium salt.

7. A compound-having the formula:

wherein M is a pharmacologically acceptable cation of a base.

No references cited.

7. A COMPOUND HAVING THE FORMULA: